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| New Immune Modulator Could Transform Treatment Strategy for Rheumatoid Arthritis and Ulcerative Colitis |
A groundbreaking clinical trial is set to commence this quarter, marking the first of its kind in the pursuit of regulating activated T cells to mitigate inflammation and tissue damage in individuals dealing with moderate to severe ulcerative colitis (UC). This trial builds upon a growing body of research involving checkpoint agonists and their potential in autoimmune and inflammatory diseases, including the likes of rheumatoid arthritis (RA).
The United States currently harbors around 1.5 million individuals grappling with inflammatory bowel disease (IBD), a chronic condition that affects the mucosa of the large intestine, colon, and rectum. Strikingly, over 50% of UC patients report that the disease significantly impacts their lives, surpassing the effects of conditions like asthma, migraines, and even rheumatoid arthritis. Although treatment options exist, only an estimated one in four UC patients experience clinical remission after a year of treatment.
The Promise of the PD-1 Pathway for UC
Researchers are delving into the realm of anti-PD-1 (programmed cell death protein-1) antibodies as a potential breakthrough to address the "effectiveness ceiling" frequently observed in UC. Just like rheumatoid arthritis, UC is an autoimmune disease primarily driven by T cells, making it an ideal candidate for monoclonal antibody intervention. Studies reveal that in inflamed tissue, up to 40% of T cells in UC's lamina propria and 80% of T cells in RA's synovium exhibit high activation levels and express PD-1 compared to healthy tissues.
In inflammatory diseases such as RA and UC, the immune system becomes overactive, and the body's natural regulatory mechanisms falter. Checkpoint agonists, like PD-1 agonists, target activated T cells within inflamed tissue and the peripheral regions. They function by reigning in uncontrolled inflammation, thus restoring immune equilibrium.
The PD-1 pathway plays a pivotal role in governing various immune cell types, encompassing two pathologically distinct T cell subtypes relevant to autoimmune and inflammatory diseases.
Firstly, effector T cells, primarily found in inflamed tissue, become PD-1high when they express heightened PD-1 levels. These cells release inflammatory cytokines, leading to tissue damage and perpetuating the inflammatory cycle.
The second set of cells comprises follicular helper T cells (Tfh) and peripheral T helper cells (Tph), both expressing elevated PD-1 levels, predominantly located in lymph nodes, spleen, and inflamed tissues. If left unchecked, these cells trigger an immune system response, worsening inflammation and causing tissue damage.
PD-1high T cells are the most pathogenic, making them promising targets for reducing immune system activation.
PD-1 Agonists Hold Promise for UC and RA
AnaptysBio is investigating rosnilimab, designed to target PD-1+ T cells, impacting critical factors in UC and RA. Unlike many existing treatments, which generally target a single disease mechanism, a PD-1 agonist can address multiple mechanisms concurrently, offering a more comprehensive approach.
This monoclonal antibody has a unique membrane-proximal binding imprint on PD-1, facilitating the clustering of immune cells, enabling potent agonist and exhaustion activity. Rosnilimab has the potential to reduce inflammation and tissue damage, potentially breaking through the efficacy limits in moderate-to-severe rheumatoid arthritis and ulcerative colitis.
In a phase 1 trial with healthy volunteers, rosnilimab demonstrated excellent tolerability and safety while showcasing a robust and sustained reduction in peripheral PD-1+ T cells over 30 days. It also displayed a favorable pharmacokinetic profile, with an estimated half-life of 2 weeks for both subcutaneous and intravenous administration routes.
Anaptys anticipates releasing high-quality data from its global Phase 2b trial in RA in mid-2025 and high-quality data from its global Phase 2 trial in UC in the first half of 2026. Stay tuned for further developments in this groundbreaking study.
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